Teaching an old drug new tricks : exploring formulation and route of delivery methods for repurposing drugs to treat CNS diseases

A major barrier to the treatment of central nervous system delivery is the ability to target drug delivery to the brain. The brain is protected by the blood-brain barrier, making it difficult for both small and especially large molecule drugs to reach their sight of action. With recent advancements in high throughput screening, some already marketed drugs have been found to be active in treating central nervous system diseases such as glioblastoma multiforme (GBM), however, some of these drugs are insufficient in their current forms to reach the brain and treat the disease. Nasal drug delivery is a promising route of delivery for treating central nervous system disease as it has shown the ability to directly transport drugs to the brain, bypassing the blood-brain barrier. Critical aspects to using nasal drug delivery to treat central nervous system diseases are the ability to target the formulation to specific sites in the nasal cavity as well as the ability of formulations to drive transport to the brain. In addition to nasal drug delivery, some drugs can benefit from improvements in bioavailability orally to increase brain exposure. Amorphous solid dispersions are a technique widely used to improve the bioavailability of the poorly-water soluble drugs however they are limited in their use for highly lipophilic drugs due to drug loading limitations. This research focuses on better understanding nasal drug delivery to leverage ways to better target sites in the nasal cavity. In addition to this targeting research, research that supports the in vitro tests for analyzing and assessing nasal drug delivery devices has been performed. Personalized nasal drug delivery in 3D-printed casts is shown to be a superior method for targeting a particular region of the nasal cavity due to the variation in individual’s nasal geometry. A large focus of the research has been to repurpose atovaquone for the treatment of glioblastoma. This research provides evidence of the benefits a new formulation strategy which incorporates a spontaneously emulsifying component into the classical amorphous solid dispersion to overcome its limitations with the highly lipophilic nature of atovaquone. The improved formulation alongside results showing activity of atovaquone against GBM present a promising repurposing strategy for atovaquone to be used in the treatment of GBM